Many of the investigations in this genetic epidemiology project arise from observations in families at high risk of cancer or in other etiologic studies. Further analyses of a case-control study of 718 non-Hispanic white patients with cutaneous melanoma from melanoma clinics in Philadelphia and San Francisco showed modest, non-significant decreased risk of melanoma among susceptible individuals who used sunscreens most of the time. Young women were the individuals most likely to use tanning beds, and use was related to melanoma risk. Those who used tanning beds were more likely to have melanomas in sites not usually exposed to sun. These observations may help explain the increasing rates and changing distribution of melanoma among young women in the general population. Questionnaire data, tumor, and DNA from a case-control study of 183 incident melanoma cases and 179 controls conducted in North-Eastern Italy, showed a strong association between germline variants in the melanocortin-1 receptor (MC1R) gene and melanoma with somatic mutations in the BRAF oncogene, in subjects with melanoma arising on sun exposed areas of the body and with limited chronic solar damage. We confirmed this association in an independent population. Data from other Mediterranean populations have been collected and harmonized to extend the analyses of association between melanoma risk and several risk factors, also including immune-related genes. In this combined sample, we identified suggestive evidence for a role of telomere-related genes in the etiology of melanoma. Melanoma tissue specimens have been collected and analyses of melanoma lesions in relation to sun exposure, body site, nevi count, susceptibility genes and other factors is planned. One of the potential pathways that leads to the development of melanoma includes the loss of regulation of common melanocytic nevi, which acquire atypic or dysplastic characteristics that can further evolve in neoplasia. To study this pathway, we are currently collecting multiple tissue samples of normal skin, common melanocytic nevi, dysplastic nevi, melanoma and metastasis from melanoma from the same subjects from Italy and Spain. We are planning to study the expression and presence of mutations in multiple genes of the cell cycle, and transduction pathways in the serial tissue samples and germline DNA to explore the mechanisms involved in melanoma development through nevi. In addition, we are developing a new melanoma tissue-based study to identify clinically and etiologically relevant subtypes of melanoma. We plan to prospectively identify and enroll 1,500 primary melanoma patients diagnosed at University Hospitals Case Medical Center (UHCMC)/Case Comprehensive Cancer Center (Case CCC). We will classify melanomas into molecular subtypes using an integrated tumor profiling approach and will associate each molecular subtype with known melanoma risk factors (including both genetic and environmental), host pigmentation characteristics, and clinical characteristics and outcomes. Currently, we are conducting a pilot study to test the technical feasibility of this study. We have collected fixed tumor blocks from 16 melanoma patients and conducted gene expression profiling analyses using RNA extracted from these tumors. We are conducting bioinformatic analyses to classify these tumors into molecular subtypes and will associate the subtypes with clinical and risk factors. In the meantime, we continue to enroll patients and obtain permission to obtain tumor blocks. Relatives of 365 of the glioma cases from a DCEG comprehensive case-control study of adults with brain tumors were interviewed about personal/family medical history and other risk factors. Chordoma is a rare primary malignant bone tumor that arises mainly in the axial skeleton from rests of embryonic notochordal stem cells that failed to undergo normal regression. An expanded project has been developed to collect personal and family medical history, buccal cells and slides of tumor tissue from sporadic chordoma patients from throughout the United States and Canada. The project will collect up to 400 patients diagnosed with chordoma at any age and anatomic site. Using buccal cell DNA extracted from 100 sporadic chordoma patients we have recruited in this study, we evaluated copy number variations (CNVs) and rare sequence variants in the T gene, which is the only susceptibility gene for chordoma identified so far.Alterations in the normal microbiome are increasingly recognized to play a role in human disease. Using protocols adapted from the NIH Human Microbiome Project, we are planning pilot studies to evaluate differences in the oral microbiome between smokers and nonsmokers. Pilot studies will be conducted in collaboration with investigators from the School of Medicine and Dentistry, University of Rochester. We collaborated with Yale University Tissue Microarray (TMA) core facility and successfully built TMAs of invasive tumors collected from the Polish Breast Cancer Study. Analyses of immunohistochemically (IHC) stained tumors (N=842) for 18 molecular markers involved in hormone biosynthesis, metabolism, and receptor mediated pathways suggested that risk factors for breast cancer may vary by molecular subtypes and by hormone pathways characterized by co-expression of the hormonal markers. In addition to the analysis of invasive tumors, we are also evaluating the morphology and molecular characteristics of terminal duct lobular units (TDLUs), the structures from which breast cancers arise, in breast cancer cases. We found that TDLU involution was significantly less pronounced in breasts containing core basal phenotype (CBP) tumors as compared to luminal tumors. We are developing multiple international collaborations to confirm and extend these findings using materials from other studies. We have also analyzed ER, PR, CK5, and EGFR expression in normal TDLUs in 150 Polish breast cancer cases and found that TDLUs near breast cancers reflected field effects, whereas those at a distance demonstrated influences of breast cancer risk factors on at-risk breast tissue. In addition to TMA analyses of candidate markers in fixed tissues, we have conducted gene expression profiling analyses in both tumor and adjacent normal tissues from a subset of Polish breast cancer cases. We are currently analyzing the expression profiling data to identify molecular signatures for TDLU involution and parity. Recently, we have developed a new tissue-based breast cancer study in Hong Kong, in which we plan to collect breast tumor and adjacent normal tissues from up to 1,000 breast cancer cases with the goal of identifying molecular changes that are related to risk and clinical factors for breast cancer subtypes among Chinese women in Hong Kong.We are continuing to conduct studies using the Swedish linked registry data to define hematologic malignancies that co-aggregate in families, to clarity the relationship between immune and inflammatory conditions (based on hospitalization records) and hematologic malignancies. We recently demonstrated that relatives of patients with chronic myeloid leukemia were not at increased risk for hematologic cancer or other solid tumors. This contrasts with the strong familial aggregation seen for other hematologic tumors and their pre-cursor traits. In a large follow-up study of patients with MGUS (monoclonal gammapothy of undetermined significance) for up to 30 years, we found significant variation in risk of lymphoid and myeloid malignancies was assocated with an abnormal free light chain ratio and immunosuppression in addition to known risk factors. This will allow the stratification of MGUS patients into high and low risk.